Molecular basis for resistance to the anticancer drug cisplatin in Dictyostelium

The efficacy of the widely used chemotherapeutic drug cisplatin is limited by the occurrence of drug-resistant tumour cells. To fully exploit the pote ntial of this drug in cancer therapy, it is imperative to understand the mo lecular basis of cisplatin resistance. Using an insertional mutagenesis tec hnique in cells of Dictyostelium discoideum, we have identified six genes w hich are involved in cisplatin resistance. None of these genes has been pre viously linked to resistance to this drug. Several of these genes encode pr oteins that are involved in signal transduction pathways which regulate cel l death, cell proliferation or gene regulation. The resistance of these mut ant strains is specific for cisplatin, since deletion of these genes does n ot confer resistance to other DNA-damaging agents. Significantly, the disru ption of three of these genes, encoding the sphingosine-1-phosphate lyase, the RegA cAMP phosphodiesterase and a phosphatidylinositol-4-phosphate 5-ki nase, also results in abnormalities in the multicellular development of thi s organism, although there is no change in the rate of mitotic cell growth. This study has identified previously unsuspected molecular pathways which function in the cellular response to cisplatin and are required for normal morphogenesis, and underscores the complexity of the cellular response to c isplatin. These pathways provide potential targets for modulating the respo nse to this important drug.